Circulating nucleic acids damage DNA of healthy cells by integrating into their genomes

Abstract

Whether nucleic acids that circulate in blood have any patho-physiological functions in the host have not been explored.We report here that far from being inert molecules, circulating nucleic acids have significant biological activities of their own that are deleterious to healthy cells of the body. Fragmented DNA and chromatin (DNAfs and Cfs) isolated from blood of cancer patients and healthy volunteers are readily taken up by a variety of cells in culture to be localized in their nuclei within a few minutes. The intra-nuclear DNAfs and Cfs associate themselves with host cell chromosomes to evoke a cellular DNA-damage-repair-response (DDR) followed by their incorporation into the host cell genomes. Whole genome sequencing detected the presence of tens of thousands of human sequence reads in the recipient mouse cells. Genomic incorporation of DNAfs and Cfs leads to dsDNA breaks and activation of apoptotic pathways in the treated cells. When injected intravenously into Balb/C mice, DNAfs and Cfs undergo genomic integration into cells of their vital organs resulting in activation of DDR and apoptotic proteins in the recipient cells. Cfs have significantly greater activity than DNAfs with respect to all parameters examined, while both DNAfs and Cfs isolated from cancer patients are more active than those from normal volunteers. All the above pathological actions of DNAfs and Cfs described above can be abrogated by concurrent treatment with DNase I and/or anti-histone antibody complexed nanoparticles both in vitro and in vivo. Taken together, our results suggest that circulating DNAfs and Cfs are physiological, continuously arising, endogenous DNA damaging agents with implications to ageing and a multitude of human pathologies including initiation of cancer.

Circulating nucleic acids: An analysis of their occurrence in malignancies

“…This indicates that stretches of nucleic acids may change the expression levels of certain genes in otherwise healthy cells, thereby promoting invasion and metastasis (20). This may lead to mutations and subsequent malignant transformation in these cells, a theory termed as genometastasis (9,88,89). The mechanism of cancer dissemination in the context of CNAs is not fully understood.…”

Zirkulierende Nukleinsäuren – ein neues Universum in der laboratoriumsmedizinischen Diagnostik

“…In experimentellen Studien wurde für cfDNA in synthetisierten Nukleosomen eine hocheffiziente Transfektionsrate bis zu 35% sowie ein nukleärer Transport gezeigt. Auch der Verbleib im Zellkern konnte dokumentiert werden [13,14] [19]. Auch bei Myokardinfarkt und Stroke wurde cfDNA als prognostischer Marker identifiziert und korrelierte in der Höhe mit der Auslenkung klinisch-chemischer Parameter [20][21][22].…”

A sejten kívüli szabad DNS felszabadulásának és degradációjának in vivo elemzése

“…Megállapították, hogy a DNáz-I adása önállóan nem, csak a proteázokat tartalmazó mixszel együtt adva váltotta ki antitumor effektusát a kezelést követő 21. naptól. Egy tanulmánynak 2015-ben sikerült bebizonyítania, hogy egészséges és rákos betegekből származó szabad DNS-és kromatinfragmentumok képesek bejutni egér fibroblast sejtekbe és rövidesen a sejtmagba is [39]. Ez volt az első tanulmány, mely leírta, hogy a fragmensek mint mobilis genetikai elemek in vitro és in vivo is képesek integrálódni a genomba.…”